Hadron treatment planning with adequate biological weighting

ABSTRACT

Treatment planning methods are provided that determine the variability of relative biological effectiveness (RBE) along a beam line and calculate, among other things, what intensity of hadron beam such as a proton or a carbon ion beam should be applied to achieve a desired biological dose at treatment site of a patient afflicted with a medical condition. Typically, three or four RBE values at three or four corresponding spacially-dispersed intervals along the beam line are calculated. In one embodiment, two RBE values for the spread-out Bragg peak (SOBP) region of the treatment site; one for the proximal section and one for the declining distal section is calculated. A third and different RBE value may be determined for the distal edge region of the SOBP. A fourth value may also be calculated for a pre-SOBP region.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. 119(e) of U.S.Provisional Application No. 60/786,402, filed Mar. 28, 2006, thedisclosure of which is incorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is generally related to methods of treatment planningusing radiotherapy, and more particularly to methods of treatmentplanning with adequate biological weighting using hadron and/or protonbeam radiotherapy.

2. Related Art

In recent years there has been a steady increase in clinical use of highenergy hadron beams for patients afflicted with tumors and other medicalconditions. It has been long known that protons differ from conventionalradiation (photons, electrons) in their biological effectiveness. Thatis, to cause the same biological effect a lower dose of protons isrequired. Therefore, protons are more biologically effective. Therelative biological effectiveness (RBE) is defined as the ratio of doseof reference radiation to the proton dose required to achieve the samebiological effect.

In current clinical practice with therapeutic proton beams, a single RBEvalue (typically 1.1) is applied to all treatment plans, irrespective ofdepth of penetration, tissue, or any other particulars of the treatment.This is because previous studies indicated that RBE values were small inmagnitude and because the variability of RBE with treatment parameterswas believed to be within 10-20%. It was concluded that this variabilitywas small relative to uncertainties associated with RBE values. Newstudies, however, reveal that the RBE variations can be as large as100-300%, especially in the penumbra of the treatment volume delineation(“TVD”), e.g., the outline of the volume that conforms to the shape ofthe tumor.

Proton radiotherapy may use either mono-energetic proton beams orpoly-energetic proton beams. Mono-energetic proton beams arecharacterized by a peak in their depth-dose distribution. This so-calledBragg peak is a result of an increasing energy deposition with the depthof penetration, leading to a maximum at the end of range of the protonbeam. To obtain a good physical dose distribution for radiotherapyapplications, the Bragg peak is spread out by passive or active beammodulation techniques to cover the target volume of a treatment site.Modulated beam profiles have a central flat region, which is used fortreatment. A passive beam modulation technique utilizes scatteringmaterial placed upstream to change the beam energy. An active beammodulation technique changes the beam energy electronically.

Poly-energetic proton beams are characterized by variations in theamounts of energy delivered and by a three-dimensional localization ofthe dose. Moreover, non-uniform dose distributions from eachpoly-energetic proton beam may superimpose to give a desired dose in atarget volume.

Beam modulation generates a broad spectrum of energies within the targetvolume, with the mean energy of protons decreasing with penetrationdistance. This results in a corresponding variation in linear energytransfer (LET), which increases with the depth of penetration. Abiological dose deposited by the protons can be described as a productof proton fluence and LET. Thus, in proton beam radiotherapy a highlyconformal high dose region is achieved by varying the proton fluence,and the energy spectrum, which is the essence of beam modulation. Thishighly conformal high dose region is the so-called spread-out Bragg peak(SOBP).

Determination of proton RBE at different points along the SOBP has beendone in many centers, such as Cyclotron Research Center at Louvain-LaNeuve and TRIUMF Cyclotron Research Center. Data has been reported onmodulated proton beams with energies less than 100 MeV. Theseexperiments used different approaches to assess the proton RBE, but allof them show that the RBE increases with depth within SOBP, with valuesranging from 1.1 to 2.5.

Proton RBE depends on a number of factors including the type of tissueand the biological end point, the initial proton energy, the energyspread of the input proton beam, the depth of beam penetration, and thebeam modulation technique. The RBE has been shown to increase with depthwithin the SOBP both theoretically and experimentally. This is partiallyattributed to the fact that the average proton energy decreases withdepth within the SOBP. There are fewer investigations of the regionbeyond the distal point of the SOBP. These studies conclude that the RBEvalues continue to increase at the declining distal edge of the SOBP.

Recent studies irradiated human tumor SCC25 cells with a 65-MeV protonbeam. Five positions along the beam line were simulated using Perspexplates of different thickness: one position, corresponding to the beamentrance, with 2 mm thick perspex, two along the SOBP at 15.6 and 25 mm,and two more measurements at the declining distal edge at 27.2 and 27.8mm. Clonogenic survival of the irradiated cells and of their progeny wasdetermined at various dose values at each position. Cobalt 60(hereinafter, “^(α)Co”) γ-rays were used as the reference radiation inthis study.

RBE values obtained in this study increased with increasing depth. Atthe proximal part of SOBP, the RBE was evaluated to be close to 1.0. Itreached the 1.2 value at the distal part of SOBP. Within the decliningedge it continued to increase, and reached the value of about 1.4 at27.2 mm, and 2 at 27.8 mm, where the relative dose was about 50% of thatat the peak value. These RBE values were evaluated at the survival levelgiven by 2 Gy γ-rays. For the progeny of irradiated cells, the RBEvalues were similar. The incidence of delayed effects increased withdose and with the depth within the beam. The results of this study showthat at the distal declining edge of the beam, the RBE values increasesignificantly to an extent that is of practical significance when theregion of treatment volume is close to sensitive tissues.

A second study was performed using the 62-MeV proton beam of the CATANA(Centro di Adro Terapia e Applicazzioni Nucleari Avanzati) facility.Cell survival of a resistant HTB140 human melanoma cell line was studiedusing various biological assays, at several depths along the SOBP, andat the declining distal edge. The three different assays used in thisstudy were the clonogenic assay, the microtetrasolium assay, and thesulforhodamine B assay. To simulate different positions along the beamline, Perspex plates of various thicknesses were interposed. Cellsamples were irradiated at 6.6, 16.3, 25, and 26 mm depths. The distalend of SOBP was at the depth of 25 mm that had a corresponding 102±3%relative dose, while the relative dose along the declining distal edgeat 26 mm was 32±4%.

Surviving fractions at 2 Gy (SF2) were obtained throughout the wholeSOBP, which indicated high level of radio-resistance of these cells. TheRBE at 2 Gy was used to analyze the efficiency of proton irradiation toinactivate cells as compared to conventional γ-ray radiation.

The results of this study again showed considerable increase in RBEvalues when approaching the distal end of SOBP. It was found that at thedeclining distal edge of SOBP, where the relative dose was ≈32%, thekilling ability of protons was close to that observed at the distal endof SOBP, where the relative dose was ≈102%. The RBE at this depth ondeclining distal edge was found to be close to 4, using the clonogenicassay, and close to 3, using the sulforhodamine B assay. For reference,the RBE at the proximal part of SOBP was found to be close to 1.3, usingboth clonogenic and sulforhodamine B assays.

Results of the two studies discussed above evidence the importance ofadditional investigations of RBE along the SOBP, and in particular, atits declining distal edge. These findings also establish the necessityof development of treatment planning methods, which will incorporateadequate proton RBE's.

SUMMARY OF THE INVENTION

The invention satisfies the foregoing needs and avoids the drawbacks andlimitations of the prior art by providing a system and methods for atreatment planning that determines the variability of RBE along the beamline and calculates, among other things, what intensity of proton beamshould be applied to achieve a desired biological dose at treatment siteof a patient afflicted with a medical condition.

In one aspect, a method for ensuring optimal biological effectiveness ofa treatment beam at a treatment site of a patient is provided thatincludes the steps of determining a variability of relative biologicaleffectiveness (RBE) along a line of each of a plurality of hadron beams,calculating RBE values at a plurality of sections of a spread-out Braggpeak (SOBP) associated with the treatment site, wherein the calculatingtakes into account the determined variability, and adjusting anintensity and energy of each of the plurality of hadron beams at each ofthe plurality of sections of the spread-out Bragg peak (SOBP) based onrespective calculated RBE values for each of the plurality of sectionsto provide a calculated dose distribution for each of the plurality ofsections, wherein the plurality of sections include a proximal part ofSOBP area of the treatment site, a distal part of the SOBP, and adeclining distal edge part of the SOBP, and wherein the calculated dosedistributions superimpose to provide a desired dose at the treatmentsite.

In another aspect, a method for ensuring adequate biologicaleffectiveness at a treatment site of a patient is provided that includesthe steps of determining a variability of relative biologicaleffectiveness (RBE) along a line of each of a first proton beam, asecond proton beam, a third proton beam, and a fourth proton beam,calculating a first RBE value at a pre-plateau part of a spread-outBragg peak (SOBP) of the treatment site, a second RBE value at aproximal part of SOBP, a third RBE value at a distal part of the SOBP,and a fourth RBE value at a declining distal edge part of the SOBP. Themethod also includes the steps of adjusting an intensity and energy ofthe proton beam at the pre-plateau part of the SOBP based on the firstRBE value to provide a first dose distribution, adjusting an intensityand energy of the proton beam at the proximal part of the SOBP based onthe second RBE value to provide a second dose distribution, adjusting anintensity and energy of the proton beam at the distal part of the SOBPbased on the third RBE value to provide a third dose distribution, andadjusting an intensity and energy of the proton beam at a decliningdistal edge part of the SOBP based on the fourth RBE value to provide afourth dose distribution, wherein the first, second, third and fourthdose distributions superimpose to provide a desired dose at thetreatment site.

In another aspect, a method for ensuring adequate biologicaleffectiveness at a treatment site of a patient is provided that includesthe steps of defining geometric parameters of the treatment site,optimizing a biological dose distribution taking into account differentrelative biological effectiveness (RBE) values at a plurality ofsections associated with the treatment site characterized by aspread-out Bragg peak (SOBP) and as defined by the geometric parameters,and delivering an optimized biological dose by hadron radiotherapy tothe plurality of sections, wherein the plurality of sections include adeclining distal edge part of the SOBP and at least one of the followingparts: a proximal part of the SOBP, a distal part of the SOBP.

In another aspect, a method for delivering a biological dose at atreatment site of a patient is provided that includes the steps ofdetermining a variability of relative biological effectiveness (RBE)along a line of each of a plurality of hadron beams, calculating RBEvalues at a plurality of sections of a spread-out Bragg peak (SOBP)associated with the treatment site, wherein the calculating takes intoaccount the determined variability, and adjusting an intensity andenergy of each of the plurality of hadron beams at each of the pluralityof sections of the spread-out Bragg peak (SOBP) based on respectivecalculated RBE values for each of the plurality of sections to provide acalculated dose distribution for each of the plurality of sections,wherein the plurality of sections include a declining distal edge partof the SOBP and at least one of: a proximal part of the SOBP, a distalpart of the SOBP and a pre-plateau portion of the SOBP, and wherein thecalculated dose distributions superimpose to provide a desired dose atthe treatment site.

In yet another aspect, an apparatus for ensuring optimal biologicaleffectiveness of a treatment beam at a treatment site of a patient isprovided that includes a first component to determine a variability ofrelative biological effectiveness (RBE) along a line of each of aplurality of hadron beams, a second component to calculate RBE values ata plurality of sections of a spread-out Bragg peak (SOBP) associatedwith the treatment site, taking into account the determined variability,and a third component to adjust an intensity and energy of each of thehadron beams at each of the plurality of sections of the spread-outBragg peak (SOBP) based on respective calculated RBE values for each ofthe plurality of sections to provide a calculated dose distribution foreach of the plurality of sections, wherein the plurality of sectionsinclude a proximal part of SOBP area of the treatment site, a distalpart of the SOBP, and a declining distal edge part of the SOBP, andwherein the calculated dose distributions superimpose to provide adesired dose at the treatment site.

Additional features, advantages, and embodiments of the invention may beset forth or apparent from consideration of the following detaileddescription, drawings, and claims. Moreover, it is to be understood thatboth the foregoing summary of the invention and the following detaileddescription are exemplary and intended to provide further explanationwithout limiting the scope of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are included to provide a furtherunderstanding of the invention, are incorporated in and constitute apart of this specification, illustrate embodiments of the invention andtogether with the detailed description serve to explain the principlesof the invention. No attempt is made to show structural details of theinvention in more detail than may be necessary for a fundamentalunderstanding of the invention and the various ways in which it may bepracticed. In the drawings:

FIG. 1 is an exemplary graph showing depth dose distribution for aspread-out Bragg peak (SOBP), according to principles of the invention.

FIG. 2 is a flow diagram showing steps of treatment planning, accordingto principles of the invention;

FIG. 3 is a relational block diagram showing various exemplarycomponents of an embodiment of the invention;

FIG. 4 is a combined relational block diagram and flow diagram of anembodiment of the invention, showing exemplary components and exemplarysequencing of processing; and

FIG. 5 is a flow diagram showing steps of an embodiment of using theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The embodiments of the invention and the various features andadvantageous details thereof are explained more fully with reference tothe non-limiting embodiments and examples that are described and/orillustrated in the accompanying drawings and detailed in the followingdescription. It should be noted that the features illustrated in thedrawings are not necessarily drawn to scale, and features of oneembodiment may be employed with other embodiments as the skilled artisanwould recognize, even if not explicitly stated herein. Descriptions ofwell-known components and processing techniques may be omitted so as tonot unnecessarily obscure the embodiments of the invention. The examplesused herein are intended merely to facilitate an understanding of waysin which the invention may be practiced and to further enable those ofskill in the art to practice the embodiments of the invention.Accordingly, the examples and embodiments herein should not be construedas limiting the scope of the invention, which is defined solely by theappended claims and applicable law. Moreover, it is noted that likereference numerals represent similar parts throughout the several viewsof the drawings.

It is understood that the invention is not limited to the particularmethodology, protocols, devices, apparatus, materials, applications,etc., described herein, as these may vary. It is also to be understoodthat the terminology used herein is used for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe invention. It must be noted that as used herein and in the appendedclaims, the singular forms “a,” “an,” and “the” include plural referenceunless the context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. Preferred methods, devices,and materials are described, although any methods and materials similaror equivalent to those described herein can be used in the practice ortesting of the invention. Although the description herein primarily usesprotons and proton beams for exemplary descriptions, it should beunderstood that other types of hadron radiotherapy may be employed aswell, such as carbon ion radiotherapy. Therefore, the examples andFigures include these other types of hadron radiotherapy.

One aspect of the invention provides a treatment planning method thatdetermines the variability of RBE along the proton beam line andcalculates, among other things, what intensity of proton beam should beapplied to achieve a desired dose at treatment site typically of apatient afflicted with a medical condition. FIG. 1 is an exemplary graphshowing depth versus dose distribution for a spread-out Bragg peak(SOBP), according to principles of the invention. This SOBP isassociated with a treatment site. In this embodiment, typically four RBEvalues at four corresponding spacially-dispersed intervals along thebeam line are considered, shown in FIG. 1 as sections or parts underbrackets labeled “A”, “B”, “C” and “D.” In FIG. 1, the section under thebracket labeled “A” of the irradiated volume is referred to as thepre-SOBP section. The section under the bracket labeled “B” of theirradiated volume is referred to as the proximal SOBP section. Thesection under the bracket labeled “C” of the irradiated volume isreferred to as the distal SOBP section, and the section under thebracket labeled “D” of the irradiated volume is referred to as thedeclining distal SOBP section. The curve labeled 105 represents aproton's depth dose profile after a plurality of individual proton beamshave been modulated to yield the constant dose region referred to as theSOBP. The curves labeled as 110 a-110 n represent depth dose profiles ofa subset of proton beams whose energies and intensities have beenmodulated to yield the constant dose region referred to as the SOPBregion. In some embodiments, fewer than four sections may be considered.

Illustratively, the method may determine two RBE values for the SOBPregion (sections B and C in FIG. 1) of the treatment site; one for theproximal section B, and one for the distal section C. A third anddifferent RBE value may be determined for the declining distal edgeregion (section D in FIG. 1). Determining the third RBE value (sectionD) is often important to take into account that the level of cellkilling several millimeters beyond the distal part (at low energies) isstill comparable with that at the proximal part of the SOBP region. Athigher energies (>200 MeV), determination of the RBE in section D may beeven more essential, because the spatial extent of this section cantypically be a couple of centimeters long.

Determination of the RBE in section A (i.e., the pre-plateau section)may also be of special significance, although not always necessary. Thissection falls in the normal tissue area, and it is known that thebiological weighting leads to a predicted increase in normal tissuecomplication probability. Fortunately, however, there have not yet beenany clinical studies reporting substantial normal tissue complications.As outlined above, however, the combination of higher RBE values andwider distal edges of high energy beams in conformal treatment plans mayresult in this becoming a significant issue.

Regarding the RBE values associated with higher (>200 MeV) energy protonbeams, the LET of the attenuating high energy protons may beproportionally higher than that observed with the 60-66 MeV protons, andthus the RBE values in the very distal portion of the SOBP region mayalso be even higher.

Once the higher energy RBE values have been obtained, they may besubstituted into a computer executable treatment algorithm to verifywhat physical and biological dose distributions are adequate for medicaltreatment using an animal model.

An algorithm that maps the 3-dimensional biological depth-dose profileof proton therapy beams with variable incident energies may be used todetermine the RBE values at different locations along the proton'sdepth-dose profile. This algorithm typically uses a model forbio-response calculations for use in clinical applications. Both asimple phenomenological model based on α,β values (linear-quadraticmodel) and more sophisticated truck structure models (Amorphous TrackPartition (ATP) and Amorphous Track Local effect (ATL), and possiblytheir combination) may be used for accurate quantitative evaluation ofbio-response of tumors and normal tissues to proton radiation.

Biologic depth-dose profiles calculated with different models may bechecked against each other, and with the cell-survival data and, moreimportantly, against in vivo measurement results to make sure there issatisfactory agreement, and for optimization.

RBE depends on the structure of the physical energy deposition, onbiological response, and production of primary DNA lesions. RBE may alsohave significant dependence on the repair capacity of the affected cellsand tissue although the RBE of fast neutrons proved to be independent ofrepair capacity. Additionally, RBE depends on the effect level and islarger for high survival levels and decreases with decreasing survival.The linear-quadratic model is one example of a survivalparameterization, given by:

S=S ₀ e ^(−(αD+βD) ² ⁾,  (1)

with S, S₀ survival (0 indicating initial) and D the dose. SinceRBE=dose_(x-ray)/dose_(p) for the same level of effect, the ratio ofx-ray and proton a values gives the highest RBE value,

$\begin{matrix}{{RBE} = {\frac{\alpha_{p}}{\alpha_{x - {ray}}}.}} & (2)\end{matrix}$

RBE is also strongly correlated to the experimental α/β ratio. Thiscorrelation is particularly strong for carbon ions. Thus, modelsintended to calculate the RBE values typically have to include α/βratios. These arguments can also help to identify tumors that are themost important candidates for hadron therapy. These are tumors of highradio-resistance that usually can be characterized by small α/β ratioand thus show the highest RBE values since RBE is typically measuredrelative to photons. The normal tissue sparing and therefore doseescalation potential of proton therapy is particularly promising forsuch tumors.

Integration of truck structure models into clinical treatment planningalgorithms has practical limitations due to high demands for computingtime and memory. Therefore, the truck structure model for protons shouldbe simplified, which may be accomplished via the use of a similarapproximation to that used in the “local effect model,” developed andsuccessfully applied at GSI for Carbon ions. Namely, the biologicaleffect due to a single traversal (direct or indirect) of the cellnucleus by the charged particle depends weakly on the “impact parameter”(line of closest approach of the particle track to the center of thenucleus). Thus, a zero impact parameter can be used that greatly reducesthe stochastic fluctuation in energy deposition. The integrity of thiscan be carefully checked by comparison of computed survival with thedata.

In some embodiments, the invention provides for incorporating in thetreatment planning process spatial variations of cell killing within thetumor, dependence on the local energy spectrum of protons characterizedby LET, and tissue specific parameters of the phenomenological model.The model uses the biological flexibility to maximize the tumorinactivation with minimal side effects. Hence, the process may includethe use of two sets of tissue parameters; one for the planned treatmentvolume (tumor cells with α-β ratio>20), and one for the normal tissue(α/β ratio<10).

An analytic model for effective and reliable LET distributioncalculation may also be used. LET models can properly account for thesecondary particles due to inelastic nuclear interactions, which becomeincreasingly important at the higher energies of interest.Identification of the most important inelastic nuclear interactionprocesses for the proton energy spectrum under study can be provided,along with validation of the LET computations with Monte Carlosimulations. The LET dependence on tissue parameters in the models canbe mapped from the data.

To deliver a desired dose to the treatment volume, techniques fromintensity modulated proton therapy (IMPT) may be used. This treatmentmay use a plurality of pencil proton beams (or other hadron beams) todeliver intentionally non-uniform dose distributions that superimpose togive the desired dose in the target volume. A well known 2.5D IMPTtechnique may be particularly useful for such a purpose.

Moreover, the intensities of the poly-energetic pencil beams used inIMPT may be individually adapted to the proximal and distal edges of thetarget volume to yield the desired dose based at least on the respectiveRBE values previously determined for these regions. The intensities ofthe pencil beams may serve as weights, modulated across the targetvolume, based in part on the variations in the RBE values. Additionalweights may also be applied to the energies of the pencil beams, whichincrease the number of degrees of freedom and the dose shapingpotential. Additionally, for the SOBP technique, the RBE values, thatare different for the proximal and distal parts of the SOBP, as well asthe RBE value for the declining distal edge and normal tissue (section Ain FIG. 1) may be adopted into the calculation as weighting factorsfixed by the bio-response model.

Thus, according to one aspect of the invention, traditional IMRT methodsmay be used to incorporate adequate RBE values into a treatment planningprogram. IMRT methods are preferred over 3-dimensional conformalradiation therapy (3DCRT) because the intensity distribution inside asingle field is non-uniform, but when combined with the other beams theresult is an optimal dose distribution in the patient. This feature maybe most useful when taking into account the variability of RBE along thebeam line.

IMRT methods for charged particles may also be preferred overtraditional intensity modulated radiation therapy as applied to photons(IMXT) because the IMXT photon method is only two dimensional in nature.That is, the beam weights for a given field are, in general, modulatedonly in the plane perpendicular to the beam direction. This is incontrast to IMPT, for which the Bragg-peak phenomena provides threedimensional localization of the dose. This allows for modulation of asingle field beam weights (intensities and energies) not only in thelateral plane, but in transverse planes as well. Hence, IMPT has extradegrees of freedom that are utilized to effectively achieve the desireddose distribution.

As an early step of developing an IMRT treatment plan based onvariations in RBE throughout the proton beam path, various clinicalobjectives should be set, just as for any other therapy plan. This maybe done either in terms of certain dose and dose-volume requirements, orbiological indices such as tumor control probability (TCP) and normaltissue complication probability (NTCP). To fully optimize biologicaleffects of the treatment, the dose and dose-volume requirements shouldbe set in terms of biological dose (D_(BIO)), which may be defined asthe product of respective RBE value(s) and the physical dose(s)(D_(Physical)). The RBE determination methods should incorporate notonly RBE values for cell killing, but also, for example, the RBE valuesfor loss of endothelial functionality and contribution of endothelialcell damage, among other biological weighting factors. An example of amethod for proton IMRT treatment plan is known that is tailored toobtain a homogeneous “biological effect” expressed in terms of S/S₀ oflinear-quadratic model discussed above (see Eq. (1)).

IMPT treatment plans may be optimized using an “inverse” treatmentplanning approach. If D_(BIO)(r) represents the biological dose where ris the position coordinate, and a set of treatment parameters arerepresented by {w_(i)}, then formally D_(BIO)(r)=O(r){w_(i)}, where O isan operator. Satisfying clinical objectives requires inversion of thetreatment parameter-dose relationship; {w_(i)}=O⁻¹(r)D_(BIO)(r). This isthe basic idea behind the inverse planning approach used in conventionalIMRT that uses the physical dose, and where {w_(i)}'s are lateralfluence weighting factors.

There are certain physical, practical and clinical limitations inherentto the inverse planning method that may make the dose distributions andbiological indices achievable in practice different from the onesdesigned by the planner. Consequently, the variable treatment parametersmay need to be optimized to best meet the preset clinical objectives.

To judge how well the clinical objectives are being met, an “objectivefunction” may be used that encapsulates the requirements set forth bythe planner, and describes the level of deviation from the setobjectives. Naturally, the objective function will vary depending on thetreatment parameters, but should have a minimum value when the treatmentparameters are optimized. Thus, the optimization process becomes amathematics problem of minimizing the objective function once thisfunction has been constructed. Typically, during optimization a set ofoptimal energy fluences from each subfield are determined that yield thedesired dose distribution within the SOBP region of the treatment sitein the patient.

Just as the clinical objectives can be specified in terms of physicaland biological parameters, the objective function (OF) as well candepend on physical and biological variables. Thus, the clinical merit ofthe dose distribution may be expressed by

OF(D _(BIO)(r))≡OF({w _(i)})  (3)

D _(BIO) ≡RBE*D _(Physical)  (4)

IMXT algorithms are usually designed to optimize the physical dosedistribution, but IMPT algorithms should be designed to optimize thebiological dose distribution, to take into account different RBE valuespresent in proton therapy. The OF may still be taken in its common formas the normalized sum of squared dose deviations for all voxels of thevolume under consideration. Then, for example, the well known maximumdose constraint for organs at risk (OAR) can be modified and expressedas

$\begin{matrix}{{{OF}_{M\; {AX}}^{OAR}\left( \left\{ w_{i} \right\} \right)} = {\frac{1}{N^{OER}}{\sum\limits_{k = 1}^{N^{OER}}\left\lbrack {C\left( {{D_{k,{BIO}}^{OAR}\left\{ w_{i} \right\}} - D_{{MA}\; X}^{OAR}} \right)} \right\rbrack^{2}}}} & (5)\end{matrix}$

Here D_(k,BIO) ^(OAR) is the biological dose in voxel k of OAR, D_(MAX)^(OAR) is the prescribed maximum allowed dose in OAR, C is a selectionoperator such as C(x)=1 if x≧0, and C(x)=0 if x<0, and N^(OAR) is thenumber of voxels in OAR. Similarly, for the target volume the familiarOF for the minimal and maximal dose limits should be modified for theRBE optimized treatment plan. OF may take the following form for themaximal and minimal dose constraints on target volume (Equations 6 and 7respectively),

$\begin{matrix}{{{OF}_{{MA}\; X}^{Target}\left( \left\{ w_{i} \right\} \right)} = {\frac{1}{N^{Target}}{\sum\limits_{k = 1}^{N^{Target}}\left\lbrack {C\left( {{D_{k,{BIO}}^{Target}\left\{ w_{i} \right\}} - D_{{MA}\; X}^{Target}} \right)} \right\rbrack^{2}}}} & (6) \\{{{OF}_{{MI}\; N}^{Target}\left( \left\{ w_{i} \right\} \right)} = {\frac{1}{N^{Target}}{\sum\limits_{k = 1}^{N^{Target}}\left\lbrack {C\left( {{D_{{MI}\; N}^{Target}\left\{ w_{i} \right\}} - D_{k,{BIO}}^{Target}} \right)} \right\rbrack^{2}}}} & (7)\end{matrix}$

Here D_(k,BIO) ^(Target) is the biological dose in voxel k of the targetvolume, D_(MAX) ^(Target) and D_(MIN) ^(Target) are the prescribedmaximum and minimum allowed doses in the target volume. Thus, thephysician may still give the treatment prescription in terms of photondose (say in cobalt-gray equivalents) coming from vast experience withtreating with photons, the method of treatment should optimize thetreatment plan to achieve the clinical objectives through truebiological dose and effect by employing RBE values determined by acombination of methods described earlier. The methods for treatmentoptimization described herein are flexible and may be adaptedaccordingly to changes in clinical objective specification.

Inverse planning tools used in IMXT and IMPT in most cases are the same,or at least similar. The skilled artisan will therefore recognize thatwhen developing IMPT algorithms, one can use IMXT programs and/or theexisting IMXT codes as a starting point.

The conventional IMRT treatment planning process may be subdivided intosteps shown in FIG. 2, starting at step 200. FIG. 2 also shows severalexemplary components, objective function 225 that encapsulates therequirements set forth by the planner and describes or calculates thelevel of deviation from the set objectives, and dose calculation 230 ofthe treatment algorithm modules provides the necessary calculations todetermine an effective dose based in part on biological factors.

Continuing with step 205, geometrical parameters related to thetreatment site are defined, such as dimensions of the elemental fluenceamplitudes projected on the isocenter plane. At step 210, selection ofthe appropriate beam configuration is made, defining such parameters asthe number of treatment beam ports and their respective beam angles, forexample. At step 215, organ parameters, such as dose-volume constraints,and/or tissue parameters are specified. Optimization at step 220represents an iterative process of finding a set of treatment parametersthat minimizes the objective function 225, which may be defined, forexample, as in equations 3 through 7. For a set of treatment parametersat each step of iteration dose calculation component 230 may supply foreach voxel of the volume being irradiated and for each irraditationsubfield the biological dose (D_(BIO) as defined earlier in Equation 4)as input for objective function 225. Dose calculation component 230 mayuse as input the tissue parameters specified in step 215. When theoptimization loop yields a set of parameters that minimizes theobjective function 225, the corresponding output of the dose calculationcomponent 220 may be presented to the user in the form of biologicaldose volume histograms for evaluation of the treatment plan. Continuingwith step 235, the calculated dose may be applied per the treatmentplan. At step 240, the process ends.

FIG. 3 is a relational block diagram showing the separation of thetreatment planning algorithm into semi-independent modules orcomponents, according to principles of the invention. These modules maybe implemented on any suitable computer readable medium for execution.The modules include a user control module 300 for interacting with auser who may be constructing a treatment plan. A dose calculation module305 provides the necessary calculations to determine an effective dosebased in part on biological factors, as appropriate, and calls upon aproton dose calculation module 320 for treatments using proton beams(likewise other modules for other hadron beams may be called upon).

The optimization loop module 310 calls upon an optimization algorithm325 and an objective function module 330, which in turn may call upon aRBE implementation module 335 for calculating the various RBE values, asdiscussed previously. The objective function component 330 takes intoaccount the biological dose like in the examples presented by Equations3 through 7. The proton dose calculation component 320 shouldincorporate the LET and RBE determination models. This proton dosecalculation component 320 (or equivalent hadron dose module) may have inits output, as one example, a matrix D_(i,j) ^(BIO) of normalizedbiological dose values in voxel i from beam spot j, as opposed tophysical dose matrix D_(i,j) ^(BIO) of conventional treatment plans.

FIG. 4 shows exemplary components employed in the general flow of thetreatment planning process of the invention, which may be implemented ona suitable computing platform having memories, storage, processors andinput/output interfaces as is commonly known in the art. Tissue specificparameters 400 that describe the site under treatment (such as an organ,for example) may be feed into an RBE and LET determination model(s) 405,which may also determine the variability of RBE. A proton dosecalculation module 410 calculates a proton biological dose based on theRBE and LET determination. An optimization process 415 employs anoptimization loop 420 and an objective function 425 to provide anoptimized map of energies and energy fluences for treatment 430including adjusting an intensity and energy of each of the beams at eachof the plurality of SOBP sections.

FIG. 5 is a flow diagram showing steps of an embodiment of using theinvention, starting at step 500. At step 505, the geometric parameter ofthe treatment site may be defined. For example, these parameters mayinclude dimensions of the elemental fluence amplitudes projected on theisocenter plane. Other parameters such as tissue parameters may also bedefined. At step 510, the variability of relative biologicaleffectiveness (RBE) along a line of each of the plurality of beams(hadron, carbon ion, or proton beams) may be determined. At step 515,RBE values may be calculated that takes into account the determinedvariability for each of the plurality of SOBP sections. The SOBPsections may include the declining distal edge and at least one othersection of the SOBP. At step 520, the intensity and energy of theplurality of beams may be adjusted based on the calculated RBE values.At step 525, the biological dose calculations may be output for use intreating a patient by irradiation. The output may be in the form of ahistogram, for example. At step 530, the process ends.

The innovations provided by the invention typically require accurateproton dose (or other hadron dose) measurements. A reliable beamcalibration, of course, is also necessary. The desired accuracy of theproton dose measurements in radiotherapy applications is ±3%. Themeasurements are also typically required to be reproducible within ±2%.

The International Commission on Radiation Units and Measurements (ICRU)has published a proton dosimetry protocol. A proton dosimetryintercomparison based on the ICRU report 59 protocol was done at LumaLinda University Medical Center. Eleven institutions participated in theintercomparison. It was shown that use of the ICRU report 59 protocolwould result in absorbed doses being delivered to patients at theirinstitutions to within ±0.9% (one standard deviation). The maximumdifference between determined doses was less than 3%. These results wereobtained with the use of thimble ionization chambers with ⁶⁰Cocalibration factors traceable to standard laboratories. The ICRU report59 protocol has been adopted by most proton therapy centers. A thimbleionization chamber may be a practical instrument for determining thereference absorbed dose.

Various modifications and variations of the described methods andsystems of the invention will be apparent to those skilled in the artwithout departing from the scope and spirit of the invention. Anydocument or patent referred to herein is incorporated by reference.Although the invention has been described in connection with specificpreferred embodiments, it should be understood that the invention asclaimed should not be unduly limited to such specific embodiments.Indeed, various modifications of the described modes for carrying outthe invention which are obvious to those skilled in the art are intendedto be within the scope of the following claims.

1-25. (canceled)
 26. An apparatus for ensuring adequate biologicaleffectiveness at a treatment site of a patient, the apparatuscomprising: a first component to determine a variability of relativebiological effectiveness (RBE) at one or more of: a pre-plateau area ofa spread-out Bragg peak (SOBP) of the treatment site, a proximal area ofthe SOBP of the treatment site, at a distal area of the SOBP of thetreatment site, or a declining distal edge area of the SOBP of thetreatment site, wherein RBE is a ratio of a dose of reference radiationto a hadron dose required to achieve a same biological effect; a secondcomponent to calculate a first RBE value at a pre-plateau area of a SOBPof the treatment site, a second RBE value at a proximal area of theSOBP, a third RBE value at a distal area of the SOBP, and a fourth RBEvalue at a declining distal edge area of the SOBP; a third component toadjust an intensity and energy of the proton beam at the pre-plateauarea of the SOBP based on the first RBE value to provide a first dosedistribution; a fourth component to adjust an intensity and energy ofthe proton beam at the proximal area of the SOBP based on the second RBEvalue to provide a second dose distribution; a fifth component to adjustan intensity and energy of the proton beam at the distal area of theSOBP based on the third RBE value to provide a third dose distribution;and a sixth component to adjust an intensity and energy of the protonbeam at a declining distal edge area of the SOBP based on the fourth RBEvalue to provide a fourth dose distribution, wherein the first, second,third and fourth dose distributions superimpose to provide a desiredradiation dose at the treatment site.
 27. The apparatus of claim 26,wherein each component to adjust an intensity and energy of the protonbeam calculates a biological dose in voxels of each of the plurality ofareas associated with the treatment site.
 28. An apparatus for ensuringadequate biological effectiveness at a treatment site of a patient, theapparatus comprising: a first component to define geometric parametersof the treatment site; a second component to optimize a biological dosedistribution taking into account different relative biologicaleffectiveness (RBE) values at a plurality of sections associated withthe treatment site and as characterized by a spread-out Bragg peak(SOBP) and as defined by the geometric parameters, wherein RBE is aratio of a dose of reference radiation to a hadron dose required toachieve a same biological effect; and a third component to deliver anoptimized biological dose by hadron radiotherapy to the plurality ofsections, wherein the plurality of sections include a declining distaledge area of the SOBP and at least one of the following areas: aproximal area of the SOBP and a distal area of the SOBP.
 29. Theapparatus of claim 28, wherein the plurality of sections include apre-plateau area of the SOBP.
 30. The apparatus of claim 28, wherein thesecond component determines the variability of the RBE values.
 31. Theapparatus of claim 28, wherein the hadron radiotherapy includes protonbeam radiotherapy.
 32. The apparatus of claim 28, wherein the hadronradiotherapy includes carbon ion beam radiotherapy.
 33. The apparatus ofclaim 28, further comprising a fourth component to define the tissueparameters for the treatment site for use by the second component. 34.An apparatus for delivering a biological dose at a treatment site of apatient, the apparatus comprising: a first component to determine avariability of relative biological effectiveness (RBE) along a line ofeach of a plurality of hadron beams, wherein RBE is a ratio of a dose ofreference radiation to a hadron dose required to achieve a samebiological effect; a second component to calculate ABE values at aplurality of sections of a spread-out Bragg peak (SOBP) associated withthe treatment site, taking into account the determined variability; anda third component to adjust an intensity and energy of each of theplurality of hadron beams at each of the plurality of sections of theassociated spread-out Bragg peak (SOBP) based on respective calculatedRBE values for each of the plurality of sections to provide a calculatedbiological dose distribution for each of the plurality of sections,wherein the plurality of sections include a declining distal edge areaof the SOBP and at least one of: a proximal area of the SOBP, a distalarea of the SOBP, a pre-plateau area of the SOBP, and wherein thecalculated biological dose distributions superimpose to provide adesired biological dose at the treatment site.
 35. The apparatus ofclaim 34, wherein the plurality of hadron beams comprise a plurality ofproton beams.
 36. The apparatus of claim 34, wherein the plurality ofhadron beams comprise a plurality of carbon ion beams.
 37. The apparatusof claim 34, wherein the third component calculates a biological dose invoxels of each of the plurality of sections associated with thetreatment site.
 38. The apparatus of claim 34, further comprising afourth component to manage tissue specific parameters and to provide thetissue specific parameters to the first component to be used indetermining the variability of (RBE) and to provide the tissue specificparameters to the second component to calculate RBE values.
 39. Theapparatus of claim 38, wherein the tissue specific parameters includesparameters for at least one of: human fibroblasts and tumor cells. 40.The apparatus of claim 34, wherein the plurality of hadron beams includea pencil beam.
 41. The apparatus of claim 40, wherein the pencil beamcomprises a poly-energetic pencil beam.
 42. The apparatus of claim 26,wherein the biological effect includes at least any one of: cellkilling, cell repair capacity, endothelial functionality, and specificconstraints from organs at risk.
 43. The apparatus of claim 28, whereinthe biological effect includes at least any one of: cell killing, cellrepair capacity, endothelial functionality, and specific constraintsfrom organs at risk.
 44. The apparatus of claim 34, wherein thebiological effect includes at least any one of: cell killing, cellrepair capacity, endothelial functionality, and specific constraintsfrom organs at risk.